The quality of life of ALS patients has substantially improved in the past decade from better nutrition, respiratory support and a variety of complementary and alternative medicines (CAM). CAM for ALS patients is well accepted by the traditional medical community. Our long-term goal is to find a combination of therapeutic actions to slow the progressive death of motor neurons that defines ALS, turning this fatal disease into a chronic condition resembling post-polio syndrome. An important clue came from discovering mutations to the antioxidant copper, zinc superoxide dismutase in 2-3% of ALS patients. Expression of ALS-mutant SODs in transgenic mice and rats is now widely used to study the effects of both traditional as well as CAM therapies on survival. We found that the loss of zinc from SOD, which is favored by the mutations, is toxic to motor neurons by increasing nitrative stress, suggesting zinc status could link the 2% familial SOD patients with the remaining 98% of ALS patients. Our research has also shown that nitrative stress in astrocytes surrounding motor neurons contributes to the progressive death of motor neurons. With a better understanding of how SOD malfunctions to cause ALS, we have identified several novel CAM antioxidant therapies that could modulate the progression of ALS. Using a combination of cell culture and immunohistological analysis along the spinal cord, we will characterize the ability of CAM therapies to modulate disease progression in these animals - testing for benefit as well as unintended harm. Our first aim is to determine whether zinc can slow the progression of ALS in transgenic SOD rats and whether heavy metal chelation therapy unintentionally may accelerate ALS by removing zinc. Our second aim will characterize whether urate can slow ALS by decreasing nitration in astrocytes and motor neurons. Because mitochondrial dysfunction is one of the earliest signs of motor neuron damage, our final aim will characterize whether lipoic acid plus acetylcarnitine can slow the progression of ALS in transgenic rats. Our proposed studies will provide a mechanistic basis for examining how CAM therapies in general can affect the course of ALS.